Cocaine abuse is associated with an increased incidence of cerebrovascular accidents including stroke, yet the mechanism(s) by which these effects are produced is unknown. The objective of these studies will be to understand in a comprehensive manner how cocaine affects the cerebral circulation and microvascular function. Studies will be conducted in A) normal adult, B) brain-injured adult and C) neonatal animals. A) With respect to normal adult brain, our pilot data show that cocaine potentiates the cerebral blood flow response induced by systemic administration of norepinephrine. We have also found that the direct effect of cocaine on cerebral arterioles is to cause dilation, which would promote vascular injury during hypertension caused by cocaine. One hypothesis we will test, which is based on our previous studies, is that by direct effects and/or potentiation of exogenous sympathomimetic agents cocaine induces acute hypertension which results in damage to the cerebrovascular wall and subsequent activation of cyclooxygenase metabolism of arachiodonic acid. Further, we hypothesize that this cyclooxygenase activation results in the production of oxygen radicals which alter cerebrovascular reactivity, increase cerebrovascular permeability and cause brain edema. Intrinsic to these studies is that cyclooxygenase inhibitors and oxygen radical scavengers will decrease cerebrovascular injury caused by cocaine. B) With respect to studies in injured animals our preliminary results clearly show that in an experimental model of concussive brain injury the presence of cocaine causes a significantly greater post-traumatic hypotension. This hypotension will increase the likelihood of ischemic brain damage and a negative post-traumatic outcome. We will examine the course of this effect and its mechanism. With respect to occlusive vascular brain injury it is known that stroke may be precipitated by platelet thrombus formation. The literature shows that cocaine increases formation of the platelet pro-aggregatory thromboxane A2. Therefore we will determine whether cocaine promotes in vivo platelet aggregation in the cerebral microcirculation. C) It is known that cocaine enters the fetus and fetal hypertension injures the fetal brain microcirculation. Therefore the effect of cocaine administration to pregnant animals on neonatal cerebrovascular permeability and brain edema will be elucidated. Therapy with free radical scavengers, which we have recently shown to prevent or reverse hypertensive cerebrovascular injury, will also be tested. The achieve our aims we will utilize acute and chronically treated animals. Species to be examined include rabbits, mice and pregnant and non-pregnant rats. We will employ our current methodology, including in vivo microscopy, acute and chronic cranial window techniques, RIA and HPLC analysis of prostaglandin formation, laser-Doppler measurement of microvascular blood flow, radiolabeled proteins, an in vivo method for inducing platelet aggregation, cyclooxygenase inhibitors and oxygen radical scavengers. In summary, the proposed studies will utilize our current technology to increase our understanding of the direct and indirect effects of cocaine on the normal, injured and fetal cerebral microcirculation. Studies with inhibitors and radical scavengers may yield important information concerning potential therapeutic agents for preventing the cerebrovascular consequences of cocaine abuse.